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The studies reported in this chapter are discussed in the respective endpoint summaries.

Additional information

Cases of potential skin sensitisation

In a study of Baer (1973), a 66-year old white male toolmaker with reported allergic symptoms was exposed to 2 % ferric chloride solution (patch test) and showed at the 72 h reading a strongly positive reaction. Patch tests were performed with 11 different metal salts in appropriate dilutions. All metal salts, except ferric chloride, showed no association with allergic contact dermatitis for the patient. In the paper it was not clear, how sensitisation was distinguished from irritation, therefore the result was considered as weak evidence of a sensitising effect in this assessment. An additional case report on allergic contact dermatitis due to ferric chloride was published previously (Nater 1960). The patient was a 44 year-old male with a background of atopic dermatitis who was experiencing regular dermal exposure to steel particles while cleaning contaminated surfaces with high pressure equipment. Various metal compounds were tested in different solutions. No reaction was observed with 0.1 % ferric chloride, whereas a positive, concentration-dependent skin reaction was seen at higher concentrations of ferric chloride. In addition, a positive reaction was also seen after application of ferric sulphate at a relatively high concentration of 10%. There was no response following application of ferrous salts or other metal salts. The data gave evidence of sensitisation by ferric chloride and ferric sulphate in a sensitive individual.

Clinical cases

Hoppe et al (1955) reported accidental overdoses of medicinal iron in small children. Oral ingestion of ferrous sulphate from 40 to 1600 mg/kg (average value 900 mg/kg) caused death. Symptoms like vomiting, diarrhoea, mild lethargy, upper abdominal pain, pallor and hyperglycaemia with more severe clinical findings including cyanosis, stupor, acidosis, haematemesis, shock and coma were common for iron salt overdoses (Aisen 1990). The expert committee on vitamins and minerals (EVM 2003) considered that in infants, 20 mg/kg bw dose of iron is associated with gastrointestinal irritation and with systemic effects occurring up to 60 mg/kg bw. The lethal dose in children is approximately 200-300 mg/kg bw and in adults approximately 1400 mg/kg bw.

In a Kleinman et al (1981) inhalation study, volunteers were exposed for 2 hours to 75 µg/m³ of ferric sulphate (equivalent to 20 µg Fe/m³). Only five of the 38 volunteers tested showed patterns indicative of a decrement in pulmonary function. Nine of the subjects exhibited significant improvement in function. The population tested was too small to allow sophisticated multivariate statistical examinations. The data, however, suggested that the tendency for a subject to improve after ferric sulphate exposure could be related to allergy status, smoking history, or a combination of these factors. According to this study, it could be concluded that the NOAEL in humans for acute respiratory effects will be higher than 20 µg Fe/m³ for a 2-hour exposure period.

Iron shows a potential to pro-oxidant effects and this caused extensive research in humans. These include many clinical investigations regarding effects of oral (dietary) iron salts in humans and correlations to cancer. The incidences of tumours in the upper digestive tract have been reported to be negatively associated with dietary iron intake (Freng et al 1998, Zhang et al 1997). Ullen et al (1997) suggested that there is a “reversed causality” in the association between dietary iron intake and cancer. By assessing reported levels of dietary and supplementary iron intake obtained through a food frequency questionnaire in a population-based case-control study in Stockholm. These authors found that initially-positive association between supplementary iron intake and colorectal cancer was reversed when intakes 5 years prior to cancer diagnosis were subtracted. The authors suggested that the initial positive association was due to the use of iron supplements to relieve early disease symptoms of iron shortage.

Many studies have shown no harmful effects associated with ingestion of iron supplements at levels of 100-200 mg/day, generally during the second and third trimesters of pregnancy (Milman et al 1999 and references therein, EVM 2003), and suggest that this level of iron supplementation is unlikely to adversely affect human pregnancy. However other information, indicative of foetotoxicity at lower exposures, is provided by case reports following overdose. An analysis of published data on potential adverse effects due to obstetric iron overdose by oral application to pregnant women was performed Tran et al (2000). The findings in the publication are confounded by wide variations in care and deferoxamine (antidote) treatment, however the authors conclude that serum iron levels of greater than 400 µg/dL (i.e. 4000 µg/L) were associated with symptomatic overdose, spontaneous abortion, preterm delivery and maternal death. McElhatton et al (1991) reached a similar conclusion following assessment of the effects of acute iron overdose, and its treatment with deferoxamine, on the pregnancy outcome. Information was collated from records at the UK National Poisons Information Centre and Teratology Information Service, Guy’s Hospital. A total of 49 pregnant patients who took iron overdoses, and in whom the outcome of pregnancy was known, were included in the study. In 28/49 cases the dosage of iron was > 20 mg/kg/bw, whilst 20/36 had measured serum iron levels > 60 µmol/L (3350 µg/L). Of the 49 pregnancies, 43 resulted in live babies, two had spontaneous abortions (one following abdominal trauma), four elective termination. Of the live babies, three were premature and another three had abnormalities. However, the authors concluded that, as all babies with malformations were associated with overdoses after the first trimester, the malformation could not be directly related to the iron overdose (or to deferoxamine therapy, given in 2 cases where abnormalities occurred).